Modified chimeric polypeptides with improved pharmacokinetic properties

Abstract

Modified chimeric polypeptides with improved pharmacokinetics are disclosed. Specifically, modified chimeric Flt1 receptor polypeptides that have been modified in such a way as to improve their pharmacokinetic profile are disclosed. Also disclosed are methods of making and using the modified polypeptides including but not limited to using the modified polypeptides to decrease or inhibit plasma leakage and/or vascular permeability in a mammal.

1. A dimeric vascular endothelial growth factor (VEGF) antagonist, comprising two fusion proteins, each fusion protein consisting of (a) a VEGF receptor component having immunoglobulin-like (Ig) domains consisting of an Ig domain 2 of a first VEGF receptor human Flt1 and Ig domain 3 of a second VEGF receptor human Flk1; and (b) a multimerizing component. 
     
     
       2. The dimeric VEGF antagonist of  claim 1 , wherein the multimerizing component comprises an immunoglobulin domain. 
     
     
       3. The dimeric VEGF antagonist of  claim 2 , wherein the immunoglobulin domain is chosen from the Fc domain of IgG and the heavy chain of IgG. 
     
     
       4. The dimeric VEGF antagonist of  claim 3 , wherein each fusion protein comprises amino acids 27-458 of the amino acid sequence shown in SEQ ID NO:16. 
     
     
       5. A dimeric vascular endothelial growth factor (VEGF) antagonist, comprising two fusion proteins, each fusion protein consisting of (a) a VEGF receptor component having immunoglobulin-like (Ig) domains consisting of an Ig domain 2 of a first VEGF receptor human Flt1 and Ig domain 3 of a second VEGF receptor human Flk1; and (b) an Fc domain of IgG. 
     
     
       6. A composition comprising a VEGF antagonist and a carrier, wherein the VEGF antagonist comprises two fusion proteins, each fusion protein consisting of (a) a VEGF receptor component having immunoglobulin-like (Ig) domains consisting of an Ig domain 2 of a first VEGF receptor human Flt1 and Ig domain 3 of a second VEGF receptor human Flk1; and (b) a multimerizing component. 
     
     
       7. The composition of  claim 6 , wherein the multimerizing component comprises an immunoglobulin domain. 
     
     
       8. The composition of  claim 7 , wherein the immunoglobulin domain is an Fc domain of IgG. 
     
     
       9. The composition of  claim 8 , wherein each fusion protein comprises amino acids 27-458 of the amino acid sequence of SEQ ID NO:16.